Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Preimplantation genetic testing for aneuploidy screening (PGT-A) is now widely used to decrease early pregnancy loss and to increase pregnancy rates, especially in women with advanced reproductive age. Despite the improved pregnancy outcomes with PGT-A, the current technology has three major limitations that limit its clinical value. First, standard PGT-A requires invasive embryo biopsy procedures, which can cause embryo damage or demise. Second, using the few tested non-fetal cells as a surrogate for the entire embryo, current PGT-A provides only indirect and often inaccurate diagnosis of fetal chromosomal status and can falsely predict pregnancy success. Third, an extensive process of embryo culture, freezing, and thawing before embryo transfer is required, which also causes embryo loss and lowers live birth rates. To overcome these limitations, this proposal will take the first step in developing a novel live embryo imaging method for aneuploidy detection with the goal of using the tested whole embryo directly for reproduction. This biopsy-free aneuploidy screening test (“Live PGT-A”) can provide direct and accurate information on all chromosomes in the entire embryo at the earliest stage without extensive embryo culture, freezing, and thawing. Integrating complementary expertise in assisted reproduction, bioengineering, fluorescent single-molecule imaging, and (epi)genomics, this team will develop Live PGT-A in mouse early embryos and examine its safety and accuracy in detail during this grant period so it can be tested in human embryos in the future as a clinical diagnostic tool. Specifically, the following aims are proposed: 1) Develop an all-chromosome live imaging method in somatic cells; 2) Examine the degradation kinetics of fluorescent ribonucleoprotein (fRNP) in mouse embryos and demonstrate genomic and transcriptomic integrity in the tested embryos; 3) Test whether Live PGT-A results in healthy offspring. Once this technology is fully developed and the safety is fully tested in mouse embryos as proposed, it can be readily extended to determine all chromosomes in human embryos, as well as in sperm and oocytes. The proposed study is highly significant because this novel Live PGT-A method has high potentials of significantly improving birth outcomes after assisted reproduction by minimizing embryo loss and wrong diagnosis and thus could one day replace the current PGT-A practice. The technology developed here also has a wide range of scientific applications. The ability to trace multiple chromosomes at once in individual live embryos will provide new insights in many essential biological processes during early embryo development, and enable direct examination of the impact of various aneuploidy on the growth and development of the embryo.
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